A number of pediatric neurological disorders are caused by developmental anomalies that influence brain structure formation. The brain architecture is determined, in part, by the precise positioning of neurons in tightly defined regions of the brain. A number of genes that regulate this process are now known in humans and other mammals. These gene products likely work together to regulate the migration of neurons during development. We are interested in a group of these genes that determine the positioning of neuronal laminae in the cerebral cortex, hippocampus, and cerebellum. Migrating neurons respond to the Reln protein that is produced in discrete zones of the brain and is required for proper positioning of neurons. Receptors on neurons, VLDLR or ApoER2, and intracellular signaling proteins, such as Dab1, are required for the appropriate response to Reln. To determine the roles of these regulatory molecules we employ mouse genetics to analyze brain development when these genes are mutated. For instance, mice have the same phenotype whether they harbor a mutation that prevents Dab1 protein expression completely, or if they only produce a mutant form of Dab1 that fails to be tyrosine phosphorylated. This suggests that the tyrosine phosphorylation of Dab1 is required for neurons to respond to Reln. We are working towards an understanding of how these signaling molecules regulate neuronal positioning and the identification of other gene products that migrating neurons require to respond to their environment.